Chemosensitization in non-small cell lung cancer cells by IKK inhibitor occurs via NF-kappaB and mitochondrial cytochrome c cascade.

Abstract

In this study, we demonstrated with mechanistic evidence that parthenolide, a sesquiterpene lactone, could antagonize paclitaxel-mediated NF-kappaB nuclear translocation and activation by selectively targeting I-kappaB kinase (IKK) activity. We also found that parthenolide could target IKK activity and then inhibit NF-kappaB; this promoted cytochrome c release and activation of caspases 3 and 9. Inhibition of caspase activity blocked the activation of caspase cascade, implying that the observed synergy was related to caspases 3 and 9 activation of parthenolide. In contrast, paclitaxel individually induced apoptosis via a pathway independent of the mitochondrial cytochrome c cascade. Finally, exposure to parthenolide resulted in the inhibition of several NF-kappaB transcript anti-apoptotic proteins such as c-IAP1 and Bcl-xl. These data strengthen the rationale for using parthenolide to decrease the apoptotic threshold via caspase-dependent processes for treatment of non-small cell lung cancer with paclitaxel chemoresistance.

• Authors: Xianqing Jin, Lin Qiu, Dianliang Zhang, Mingman Zhang, Ziming Wang, Zhenhua Guo, Chun Deng, Chunbao Guo
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) 2009 Nov-Dec Vol. 13 Issue 11-12 Pg. 4596-607 ISSN: 1582-4934 [Electronic] England
• PMID: 19067767 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(4-methylphenylsulfonyl)-2-propenenitrile
• NF-kappa B
• Nitriles
• RNA, Messenger
• Sesquiterpenes
• Sulfones
• Transcription Factor RelA
• bcl-X Protein
• parthenolide
• Cytochromes c
• I-kappa B Kinase
• Paclitaxel

Topics

• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (enzymology, genetics, pathology)
• Cell Line, Tumor
• Cytochromes c (metabolism)
• Drug Screening Assays, Antitumor
• Enzyme Activation (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Silencing (drug effects)
• Humans
• I-kappa B Kinase (antagonists & inhibitors, metabolism)
• Lung Neoplasms (enzymology, genetics, pathology)
• Mitochondria (drug effects, metabolism)
• NF-kappa B (metabolism)
• Nitriles (pharmacology)
• Paclitaxel (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Sesquiterpenes (pharmacology)
• Signal Transduction (drug effects)
• Sulfones (pharmacology)
• Transcription Factor RelA (metabolism)
• Up-Regulation (drug effects)
• bcl-X Protein (metabolism)